Submissions for variant NM_002470.4(MYH3):c.3731C>T (p.Ala1244Val)

gnomAD frequency: 0.00054  dbSNP: rs140074626

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000295438	SCV000400347	benign	Freeman-Sheldon syndrome	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Illumina Laboratory Services, Illumina	RCV000352771	SCV000400348	likely benign	Distal arthrogryposis type 2B1	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000874040	SCV001016161	likely benign	not provided	2025-01-27	criteria provided, single submitter	clinical testing
GeneDx	RCV000874040	SCV001940032	benign	not provided	2020-09-01	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000874040	SCV004810995	likely benign	not provided	2024-03-01	criteria provided, single submitter	clinical testing	MYH3: BP4
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004800387	SCV005422875	uncertain significance	not specified	2024-10-08	criteria provided, single submitter	clinical testing	Variant summary: MYH3 c.3731C>T (p.Ala1244Val) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0008 in 251474 control chromosomes, predominantly at a frequency of 0.0016 within the Non-Finnish European subpopulation in the gnomAD database, including 1 homozygote. To our knowledge, no occurrence of c.3731C>T in individuals affected with MYH3-Related Disorders and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 321731). Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000874040	SCV001799158	likely benign	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000874040	SCV001927518	likely benign	not provided		no assertion criteria provided	clinical testing